Dogretole 200 Sustained release

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Dogretole 200 Sustained release


 



WARNINGS


serious dermatologic reactions and hla-b*1502 allele :


serious and sometimes fatal dermatologic reactions، including toxic epidermal necrolysis (ten) and stevens-johnson syndrome (sjs)، have been reported during treatment with carbamazepine. these reactions are estimated to occur in 1 to 6 per 10،000 new users in countries with mainly caucasian populations، but the risk in some asian countries is estimated to be about 10 times higher. studies in patients of chinese ancestry have found a strong association between the risk of developing sjs/ten and the presence of hla-b*1502، an inherited allelic variant of the hla-b gene. hla-b*1502 is found almost exclusively in patients with ancestry across broad areas of asia. patients with ancestry in genetically at-risk populations should be screened for the presence of hla-b*1502 prior to initiating treatment with carbamazepine. patients testing positive for the allele should not be treated with carbamazepine unless the benefit clearly outweighs the risk .


aplastic anemia and agranulocytosis:


aplastic anemia and agranulocytosis have been reported in association with the use of carbamazepine. data from a population-based case control study demonstrate that the risk of developing these reactions is 5 to 8 times greater than in the general population. however، the overall risk of these reactions in the untreated general population is low، approximately six patients per one million population per year for agranulocytosis and two patients per one million population per year for aplastic anemia. although reports of transient or persistent decreased platelet or white blood cell counts are not uncommon in association with the use of carbamazepine، data are not available to estimate accurately their incidence or outcome. however، the vast majority of the cases of leukopenia have not progressed to the more serious conditions of aplastic anemia or agranulocytosis. because of the very low incidence of agranulocytosis and aplastic anemia، the vast majority of minor hematologic changes observed in monitoring of patients on tegretol are unlikely to signal the occurrence of either abnormality. nonetheless، complete pretreatment hematological testing should be obtained as a baseline. if a patient in the course of treatment exhibits low or decreased white blood cell or platelet counts، the patient should be monitored closely. discontinuation of the drug should be considered if any evidence of significant bone marrow depression develops.



Composition:


Each Sustained release film coated tablet contains 200mg Carbamazepine



Mechanism of action:


Carbamazepine has demonstrated anticonvulsant properties.


It appears to act by reducing polysynaptic responses and blocking the


post-tetanic potentiation.


Carbamazepine greatly reduces or abolishes pain induced by


stimulation of the infraorbital nerve in cats and rats.


It depresses thalamic potential and bulbar and polysynaptic reflexes،


including the linguomandibular reflex in cats.



Pharmacokinetics :


the suspension was absorbed somewhat faster، and the XR tablet slightly slower، than the conventional tablet. The bioavailability of the XR tablet was 89% compared to suspension.


Carbamazepine in blood is 76% bound to plasma proteins. Plasma levels of Carbamazepine are variable and may range from 0.5 to 25 mcg/mL.


Following chronic oral administration of suspension، plasma levels peak at approximately 1.5 hours compared to 4 to 5 hours after administration of conventional Carbamazepine tablets، and 3 to 12 hours after administration of Carbamazepine -XR tablets.



Indications:


Epilepsy :


Carbamazepine is indicated for use as an anticonvulsant drug. In patients with the following seizure types:


-Partial seizures with complex symptomatology (psychomotor، temporal lobe). Patients with these seizures appear to show greater improvement than those with other types.


-Generalized tonic-clonic seizures (grand mal).


-Mixed seizure patterns which include the above، or other partial or generalized seizures. Absence seizures (petit mal) do not appear to be controlled by Carbamazepine.


Trigeminal Neuralgia:  Carbamazepine is indicated in the treatment of the pain associated with true trigeminal neuralgia. Beneficial results have also been reported in glossopharyngeal neuralgia.


This drug is not a simple analgesic and should not be used for the relief of trivial aches or pains.


Bipolar disorder: carbamazepine is used to treat or prevent the manic episodes associated with bipolar disorder



Dosage:


1-Epilepsy:


Adults and children over 12 years of age :


-Initial: Either 200 mg b.i.d. for tablets and XR tablets، or 1 teaspoon q.i.d. for suspension (400 mg/day). Increase at weekly intervals by adding up to 200 mg/day using a b.i.d. regimen of Carbamazepine -XR or a t.i.d. or q.i.d. regimen of the other formulations until the optimal response is obtained. Dosage generally should not exceed 1000 mg daily in children 12 to 15 years of age، and 1200 mg daily in patients above 15 years of age. Doses up to 1600 mg daily have been used in adults in rare instances.


-Maintenance: Adjust dosage to the minimum effective level، usually 800 to 1200 mg daily.


Children 6 to 12 years of age :


-Initial: Either 100 mg b.i.d. for tablets or XR tablets، or ½ teaspoon q.i.d. for suspension (200 mg/day). Increase at weekly intervals by adding up to 100 mg/day using a b.i.d. regimen of Carbamazepine -XR or a t.i.d. or q.i.d. regimen of the other formulations until the optimal response is obtained. Dosage generally should not exceed 1000 mg daily.



-Maintenance: Adjust dosage to the minimum effective level، usually 400 to 800 mg daily.


Children under 6 years of age :


-Initial: 10 to 20 mg/kg/day b.i.d. or t.i.d. as tablets، or q.i.d. as suspension. Increase weekly to achieve optimal clinical response administered t.i.d. or q.i.d.


-Maintenance: optimal clinical response is achieved at daily doses below 35 mg/kg. If satisfactory clinical response has not been achieved، plasma levels should be measured to determine whether or not they are in the therapeutic range. No recommendation regarding the safety of carbamazepine for use at doses above 35 mg/kg/24 hours can be made.


Combination Therapy: Carbamazepine may be used alone or with other anticonvulsants. When added to existing anticonvulsant therapy، the drug should be added gradually while the other anticonvulsants are maintained or gradually decreased، except phenytoin، which may have to be increased.


2-Trigeminal Neuralgia :


-Initial: On the first day، either 100 mg b.i.d. for tablets or XR tablets، or ½ teaspoon q.i.d. for suspension، for a total daily dose of 200 mg. This daily dose may be increased by up to 200 mg/day using increments of 100 mg every 12 hours for tablets or XR tablets، or 50 mg (½ teaspoon) q.i.d. for suspension، only as needed to achieve freedom from pain. Do not exceed 1200 mg daily.


-Maintenance: Control of pain can be maintained in most patients with 400 to 800 mg daily. However، some patients may be maintained on as little as 200 mg daily، while others may require as much as 1200 mg daily. At least once every 3 months throughout the treatment period، attempts should be made to reduce the dose to the minimum effective level or even to discontinue the drug.



Dosage Information :




Initial Dose



Subsequent Dose





Maximum Daily Dose






Indication





Tablet





XR





Tablet





XR





Tablet  and XR






Epilepsy


Under 6 years





10-20 mg/kg/day b.i.d. or t.i.d.





 





Increase weekly to achieve optimal clinical response، t.i.d. or q.i.d.





 





35 mg/kg/24 hr






Epilepsy


6-12 years





100 mg b.i.d. (200 mg/day)





100 mg b.i.d. (200 mg/day)





Add up to 100 mg/day at weekly intervals، t.i.d. or q.i.d.





Add 100 mg/day at weekly intervals، b.i.d.





1000 mg/24 hr






Epilepsy


Over 12 years





 



200 mg b.i.d. (400 mg/day)





 



200 mg b.i.d. (400 mg/day)





Add up to 200 mg/day at weekly intervals، t.i.d. or q.i.d.





Add up to 200 mg/day at weekly intervals، b.i.d.





1000 mg/24 hr (12-15 yr)


1200 mg/24 hr (>15 yr)


1600 mg/24 hr (adults، in rare instances)






Trigeminal Neuralgia





100 mg b.i.d. (200 mg/day)





100 mg b.i.d. (200 mg/day)





Add up to 200 mg/day at weekly intervals، t.i.d. or q.i.d.





Add up to 200 mg/day in increments of 100 mg every 12 hr





1200 mg/24 hr






Bipolar disorder





200 mg b.i.d. (400 mg/day)





200 mg b.i.d. (400 mg/day)





Increase by increments of 200 mg/day divided into   doses





Increase by increments of 200 mg/day divided into two doses





not to exceed 1600 mg/day



 



Overdose:


Signs and Symptoms:  The first signs and symptoms appear after 1 to 3 hours. Neuromuscular disturbances are the most prominent. Cardiovascular disorders are generally milder، and severe cardiac complications occur only when very high doses (greater than 60 g) have been ingested.


Treatment: Induction of vomiting، Gastric lavage. Even when more than 4 hours have elapsed following ingestion of the drug، the stomach should be repeatedly irrigated، especially if the patient has also consumed alcohol.


Measures to Reduce Absorption: Activated charcoal، laxatives.


Measures to Accelerate Elimination: Forced diuresis.


Dialysis is indicated only in severe poisoning associated with renal failure. Replacement transfusion is indicated in severe poisoning in small children.


Respiratory Depression: Keep the airways free، resort، if necessary، to endotracheal intubation، artificial respiration، and administration of oxygen.


Hypotension، Shock: Keep the patient’s legs raised and administer a plasma expander.


Convulsions: Diazepam or barbiturates.


Warning: Diazepam or barbiturates may aggravate respiratory depression (especially in children)، hypotension، and coma.


Respiration، cardiac function، blood pressure، body temperature، pupillary reflexes، and kidney and bladder function should be monitored for several days.


Treatment of Blood Count Abnormalities: If evidence of significant bone marrow depression develops، the following recommendations are suggested:


1-stop the drug


2-perform daily CBC


3-do a bone marrow aspiration and trephine biopsy immediately and repeat with sufficient frequency to monitor recovery



Side effects:


-The most severe adverse reactions have been observed in the hemopoietic system and، the liver، and the cardiovascular system.


-The most frequently observed adverse reactions، particularly during the initial phases of therapy، are dizziness، drowsiness، unsteadiness، nausea، and vomiting. To minimize the possibility of such reactions، therapy should be initiated at the lowest dosage recommended.


-The following additional adverse reactions have been reported: Aplastic anemia، agranulocytosis، pancytopenia، bone marrow depression، thrombocytopenia، leukopenia، leukocytosis، eosinophilia، anemia، acute intermittent porphyria، variegate porphyria، porphyria cutanea tarda، Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS)، Acute Generalized Exanthematous Pustulosis (AGEP)، pruritic and erythematous rashes، urticaria، photosensitivity reactions، alterations in skin pigmentation، exfoliative dermatitis، erythema multiforme and nodosum، purpura، aggravation of disseminated lupus erythematosus، alopecia، diaphoresis and onychomadesis ، hirsutism. Congestive heart failure، edema، aggravation of hypertension، hypotension، syncope and collapse، aggravation of coronary artery disease، arrhythmias and AV block، thrombophlebitis، thromboembolism (e.g. pulmonary embolism)، and adenopathy or lymphadenopathy. Abnormalities in liver function tests، cholestatic and hepatocellular jaundice، hepatitis، very rare cases of hepatic failure، Pancreatitis، Pulmonary hypersensitivity characterized by fever، dyspnea، pneumonitis، or pneumonia. Urinary frequency، acute urinary retention، oliguria with elevated blood pressure، azotemia، renal failure، and impotence ، Albuminuria، glycosuria، elevated BUN، and microscopic deposits in the  urine have also been reported ، disturbances of coordination، confusion، headache، fatigue، blurred vision، visual hallucinations، transient diplopia، oculomotor disturbances، nystagmus، speech disturbances، abnormal involuntary movements، peripheral neuritis and paresthesias، depression with agitation، talkativeness، tinnitus، hyperacusis، neuroleptic malignant syndrome. gastric distress and abdominal pain، diarrhea، constipation، anorexia، and dryness of the mouth and pharynx، glossitis and stomatitis، Scattered punctate cortical lens opacities، increased intraocular pressure ،conjunctivitis . Aching joints and muscles، and leg cramps ،Fever and chills. Inappropriate antidiuretic hormone (ADH) secretion syndrome ،Cases of frank water intoxication with decreased serum sodium (hyponatremia) and confusion ، Decreased levels of plasma calcium leading to osteoporosis .



Contraindications:


-Carbamazepine should not be used in patients with a history of previous bone marrow depression، hypersensitivity to the drug، or known sensitivity to any of the tricyclic compounds، such as amitriptyline، desipramine، imipramine، protriptyline، nortriptyline، etc.


-its use with monoamine oxidase (MAO) inhibitors is not recommended. Before administration of Carbamazepine، MAO inhibitors should be discontinued for a minimum of 14 days، or longer if the clinical situation permits.


-Coadministration of carbamazepine with nefazodone is contraindicated.



Drug interactions:


-There has been a report of a patient who passed an orange rubbery precipitate in his stool the day after ingesting Carbamazepine suspension immediately followed by chlorpromazine solution. Subsequent testing has shown that mixing Carbamazepine suspension and chlorpromazine solution as well as Carbamazepine suspension and liquid thorazidine hcl، resulted in the occurrence of this precipitate. Because the extent to which this occurs with other liquid medications is not known، Carbamazepine suspension should not be administered simultaneously with other liquid medicinal agents or diluents.


Agents That May Affect Carbamazepine Plasma Levels:


-Agents That Increase Carbamazepine Levels: aprepitant، cimetidine، ciprofloxacin، danazol، diltiazem، macrolides، erythromycin، troleandomycin، clarithromycin، fluoxetine، fluvoxamine، nefazodone، trazodone، loxapine، olanzapine، quetiapine، loratadine، terfenadine، omeprazole، oxybutynin، dantrolene، isoniazid، niacinamide، nicotinamide، ibuprofen، propoxyphene، azoles (e.g. ketoconazole، itraconazole، fluconazole، voriconazole)، acetazolamide، verapamil، ticlopidine، grapefruit juice، protease inhibitors، valproate.


Agents That Decrease Carbamazepine Levels: cisplatin، doxorubicin HCl، felbamate، fosphenytoin، rifampin، phenobarbital، phenytoin، primidone، methsuximide، theophylline، aminophylline.


Effect of Carbamazepine on Plasma Levels of Concomitant Agents:


-Decreased Levels of Concomitant Medications: acetaminophen، albendazole، alprazolam، aprepitant، buprenorphone، bupropion، citalopram، clonazepam، clozapine، corticosteroids (e.g. prednisolone، dexamethasone)، cyclosporine، dicumarol، calcium channel blockers (e.g. felodipine)، doxycycline، ethosuximide، everolimus، haloperidol، imatinib، itraconazole، lamotrigine، levothyroxine، methadone، methsuximide، mianserin، midazolam، olanzapine، oral and other hormonal contraceptives، oxcarbazepine، paliperidone، phensuximide، phenytoin، praziquantel، protease inhibitors، risperidone، sertraline، sirolimus، tadalafil، theophylline، tiagabine، topiramate، tramadol، trazodone، tricyclic antidepressants (e.g. imipramine، amitriptyline، nortriptyline)، valproate، warfarin، ziprasidone، zonisamide.


-There is a potential for increased cyclophosphamide toxicity when coadministered with carbamazepine.


-When carbamazepine is added to aripiprazole therapy، the aripiprazole dose should be doubled. When carbamazepine is withdrawn from the combination therapy، the aripiprazole dose should be reduced.


-When carbamazepine is used with tacrolimus، monitoring of tacrolimus blood concentrations and appropriate dosage adjustments are recommended.


-The use of concomitant strong CYP3A4 inducers such as carbamazepine should be avoided with temsirolimus.


-The use of carbamazepine with lapatinib should generally be avoided.


-Coadministration of carbamazepine with nefazodone is contraindicated.


Other Drug Interactions:


-Concomitant administration of carbamazepine and lithium may increase the risk of neurotoxic side effects.


-Concomitant use of carbamazepine and isoniazid has been reported to increase isoniazid-induced hepatotoxicity.


-Concomitant medication with Carbamazepine and some diuretics (hydrochlorothiazide، furosemide) may lead to symptomatic hyponatremia.


-Alterations of thyroid function have been reported in combination therapy with other anticonvulsant medications.


-Concomitant use of Carbamazepine with hormonal contraceptive products (e.g. oral، and levonorgestrel subdermal implant contraceptives) may render the contraceptives less effective because the plasma concentrations of the hormones may be decreased. Alternative or back-up methods of contraception should be considered.


-Resistance to the neuromuscular blocking action of the nondepolarizing neuromuscular blocking agents pancuronium، vecuronium، rocuronium and cisatracurium has occurred in patients chronically administered carbamazepine.



Warning:


Carbamazepine has shown mild anticholinergic activity، therefore، patients with increased intraocular pressure should be closely observed during therapy.


Because of the relationship of the drug to other tricyclic compounds، the possibility of activation of a latent psychosis and، in elderly patients، of confusion or agitation should be borne in mind.


The use of Carbamazepine should be avoided in patients with a history of hepatic porphyria (e.g. acute intermittent porphyria، variegate porphyria، porphyria cutanea tarda). Acute attacks have been reported in such patients  receiving Carbamazepine therapy.


As with all antiepileptic drugs، Carbamazepine should be withdrawn gradually to minimize the potential of increased seizure frequency.


Serious Dermatologic Reactions: Serious and sometimes fatal dermatologic reactions، including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS)، have been reported with Carbamazepine treatment. If signs or symptoms suggest SJS/TEN، use of this drug should not be resumed and alternative therapy should be considered.


SJS/TEN and HLA-B*1502 Allele: There is a strong association between the risk of developing SJS/TEN with carbamazepine treatment and the presence of an inherited variant of the HLA-B gene، HLA-B*1502.


Prior to initiating Carbamazepine therapy، testing for HLA-B*1502 should be performed in patients with ancestry in populations in which HLA-B*1502 may be present.


Hypersensitivity Reactions and HLA-A*3101 Allele: Retrospective case-control studies in patients of European، Korean، and Japanese ancestry have found a moderate association between the risk of developing hypersensitivity reactions and the presence of HLA-A*3101، an inherited allelic variant of the HLA-A gene، in patients using carbamazepine. These hypersensitivity reactions include SJS/TEN، maculopapular eruptions، and Drug Reaction with Eosinophilia and Systemic Symptoms.


Aplastic Anemia and Agranulocytosis:  Aplastic anemia and agranulocytosis have been reported in association with the use of Carbamazepine.


Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity:  Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)، also known as multiorgan hypersensitivity، has occurred with Carbamazepine.


Hypersensitivity:  Hypersensitivity reactions to carbamazepine have been reported in patients who previously experienced this reaction to anticonvulsants including phenytoin، primidone، and phenobarbital. If such history is present، benefits and risks should be carefully considered and، if carbamazepine is initiated، the signs and symptoms of hypersensitivity should be carefully monitored.


Suicidal Behavior and Ideation:  Antiepileptic drugs (AEDs)، including Carbamazepine، increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression، suicidal thoughts or behavior، and/or any unusual changes in mood or behavior.



Precautions:


-Carbamazepine should be used with caution in patients with a mixed seizure disorder that includes atypical absence seizures، since in these patients Carbamazepine has been associated with increased frequency of generalized convulsions.


-Therapy should be prescribed only after critical benefit-to-risk appraisal in patients with a history of cardiac conduction disturbance، including second and third degree AV heart block، cardiac، hepatic، or renal damage، adverse hematologic or hypersensitivity reaction to other drugs، including reactions to other anticonvulsants، or interrupted courses of therapy with Carbamazepine.


-AV heart block، including second and third degree block، have been reported following Carbamazepine treatment.


-Since a given dose of Carbamazepine suspension will produce higher peak levels than the same dose given as the tablet، it is recommended that patients given the suspension be started on lower doses and increased slowly to avoid unwanted side effects.


-Carbamazepine suspension contains sorbitol and، therefore، should not be administered to patients with rare hereditary problems of fructose intolerance.


-Caution should be exercised if alcohol is taken in combination with Carbamazepine therapy، due to a possible additive sedative effect.


-Since dizziness and drowsiness may occur، patients should be cautioned about the hazards of operating machinery or automobiles or engaging in other potentially dangerous tasks



Use in pregnancy or lactation:


Category D: Carbamazepine can cause fetal harm when administered to a pregnant woman.


Epidemiological data suggest that there may be an association between the use of carbamazepine during pregnancy and congenital malformations، including spina bifida.


Antiepileptic drugs should not be discontinued abruptly in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life.


Nursing Mothers: Carbamazepine and its epoxide metabolite are transferred to breast milk.


Because of the potential for serious adverse reactions in nursing infants from carbamazepine، a decision should be made whether to discontinue nursing or to discontinue the drug، taking into account the importance of the drug to the mother.


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